Abstract
The cerebral accumulation and cytotoxicity of amyloid beta (Aβ) is central to Alzheimer’s pathogenesis. However, little is known about how the amyloid pathology affects the global expression of brain proteins at different disease stages. In order to identify genotype and time-dependent significant changes in protein expression, we employed quantitative proteomics analysis of hippocampal tissue from the McGill-R-Thy1-APP rat model of Alzheimer-like amyloid pathology. McGill transgenic rats were compared to wild-type rats at early and late pathology stages, i.e., when intraneuronal Aβ amyloid burden is conspicuous and when extracellular amyloid plaques are abundant with more pronounced cognitive deficits. After correction for multiple testing, the expression levels of 64 proteins were found to be considerably different in transgenic versus wild-type rats at the pre-plaque stage (3 months), and 86 proteins in the post-plaque group (12 months), with only 9 differentially regulated proteins common to the 2 time-points. This minimal overlap supports the hypothesis that different molecular pathways are affected in the hippocampus at early and late stages of the amyloid pathology throughout its continuum. At early stages, disturbances in pathways related to cellular responses to stress, protein homeostasis, and neuronal structure are predominant, while disturbances in metabolic energy generation dominate at later stages. These results shed new light on the molecular pathways affected by the early accumulation of Aβ and how the evolving amyloid pathology impacts other complex metabolic pathways.
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Acknowledgements
The Cuello laboratory is grateful for the unrestricted support received from Dr. Alan Frosst, the Frosst family, and Merck Canada. This study was supported by the Canadian Institute of Health Research (MOP-102752 to A.C.C.). This work was also made possible through the Roskamp Foundation. S.D.C. is the holder of the Charles E. Frosst/Merck Research Associate position. M.F.I. was the recipient of a Biomedical Doctoral Award from the Alzheimer Society of Canada (2011–2014). A.C.C. is the holder of the Charles E. Frosst/Merck-endowed Chair in Pharmacology and a member of the Canadian Consortium on Neurodegeneration in Aging.
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S.D.C., F.C., and A.C.C. designed and supervised the research. S.D.C., G.C., T.P., J.R., M.F.I., and A.D. performed research. S.D.C., G.C., T.P., and M.F.I. analyzed data. S.D.C., G.C., F.C., and A.C.C. wrote the manuscript.
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All procedures were approved by the Animal Care Committee of McGill University and conformed to guidelines set down by the Canadian Council of Animal Care.
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One Sentence Summary: Brain proteome changes throughout amyloid pathology progression
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Do Carmo, S., Crynen, G., Paradis, T. et al. Hippocampal Proteomic Analysis Reveals Distinct Pathway Deregulation Profiles at Early and Late Stages in a Rat Model of Alzheimer’s-Like Amyloid Pathology. Mol Neurobiol 55, 3451–3476 (2018). https://doi.org/10.1007/s12035-017-0580-9
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DOI: https://doi.org/10.1007/s12035-017-0580-9